A chemoproteomic platform to quantitatively map targets of lipid-derived electrophiles

Wang, Chu; Weerapana, Eranthie; Blewett, Megan M.; Cravatt, Benjamin F.

doi:10.1038/nmeth.2759

Cited by 268 publications

(311 citation statements)

References 44 publications

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“…Energy metabolism enzymes are one of the main classes of proteins that contain highly reactive cysteines. Among them, several studies identified critical cysteine residues from the brain form of GP (22)(23)(24)(25)(26).…”

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confidence: 99%

An Isozyme-specific Redox Switch in Human Brain Glycogen Phosphorylase Modulates Its Allosteric Activation by AMP

Mathieu

Duval

Cocaign

et al. 2016

Journal of Biological Chemistry

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Edited by Jeffrey PessinBrain glycogen and its metabolism are increasingly recognized as major players in brain functions. Moreover, alteration of glycogen metabolism in the brain contributes to neurodegenerative processes. In the brain, both muscle and brain glycogen phosphorylase isozymes regulate glycogen mobilization. However, given their distinct regulatory features, these two isozymes could confer distinct metabolic functions of glycogen in brain. Interestingly, recent proteomics studies have identified isozymespecific reactive cysteine residues in brain glycogen phosphorylase (bGP). In this study, we show that the activity of human bGP is redox-regulated through the formation of a disulfide bond involving a highly reactive cysteine unique to the bGP isozyme. We found that this disulfide bond acts as a redox switch that precludes the allosteric activation of the enzyme by AMP without affecting its activation by phosphorylation. This unique regulatory feature of bGP sheds new light on the isoform-specific regulation of glycogen phosphorylase and glycogen metabolism.

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mentioning

confidence: 99%

An Isozyme-specific Redox Switch in Human Brain Glycogen Phosphorylase Modulates Its Allosteric Activation by AMP

Mathieu

Duval

Cocaign

et al. 2016

Journal of Biological Chemistry

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“…In addition to being activated by Stx-and ricin-mediated ribotoxic stress, ZAK signaling and/or expression also has been associated with cardiac hypertrophy (45,46); G 2 /M cell cycle arrest in response to gamma irradiation (47); metastasis (48); gastric, colon, and bladder cancers (49,50); doxorubicin toxicity (51); anisomycin treatment; exposure to UV irradiation (26); osmotic shock (52); and oxidative stress (53), suggesting that ZAK transduces a number of different stress responses.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Classical Mitogen-Activated Protein Kinases Is Part of the Shiga Toxin-Induced Ribotoxic Stress Response and May Contribute to Shiga Toxin-Induced Inflammation

et al. 2016

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c Infection with enterohemorrhagic Escherichia coli (EHEC) can result in severe disease, including hemorrhagic colitis and the hemolytic uremic syndrome. Shiga toxins (Stx) are the key EHEC virulence determinant contributing to severe disease. Despite inhibiting protein synthesis, Shiga toxins paradoxically induce the expression of proinflammatory cytokines from various cell types in vitro, including intestinal epithelial cells (IECs). This effect is mediated in large part by the ribotoxic stress response (RSR). The Shiga toxin-induced RSR is known to involve the activation of the stress-activated protein kinases (SAPKs) p38 and JNK. In some cell types, Stx also can induce the classical mitogen-activated protein kinases (MAPKs) or ERK1/2, but the mechanism(s) by which this activation occurs is unknown. In this study, we investigated the mechanism by which Stx activates ERK1/2s in IECs and the contribution of ERK1/2 activation to interleukin-8 (IL-8) expression. We demonstrate that Stx1 activates ERK1/2 in a biphasic manner: the first phase occurs in response to StxB1 subunit, while the second phase requires StxA1 subunit activity. We show that the A subunit-dependent ERK1/2 activation is mediated through ZAK-dependent signaling, and inhibition of ERK1/2 activation via the MEK1/2 inhibitors U0126 and PD98059 results in decreased Stx1-mediated IL-8 mRNA. Finally, we demonstrate that ERK1/2 are activated in vivo in the colon of Stx2-intoxicated infant rabbits, a model in which Stx2 induces a primarily neutrophilic inflammatory response. Together, our data support a role for ERK1/2 activation in the development of Stx-mediated intestinal inflammation.

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“…Proteomic studies revealed highly reactive cysteine residues in bGP (Cys 109 , Cys 326 , and Cys 496 ) (25)(26)(27), which can constitute potent targets of electrophilic compounds such as DTCs. Consequently, DTCs may directly modulate glycogenolysis through the modification of key cysteine residues of bGP, known to redox regulate the enzyme activity.…”

Section: Discussionmentioning

confidence: 99%

“…Rat models and recent proteomic studies suggested that brain glycogen phosphorylase is a putative target of DTC chemicals in the brain (7). In addition, this isoenzyme has been described as presenting highly reactive cysteine residues (23,(25)(26)(27). To further determine the impact of DTCs on bGP activity and glycogen metabolism in the brain, we treated mice brain extracts with thiram (Fig.…”

Section: Edited By Ruma Banerjeementioning

confidence: 99%

Molecular Mechanisms of Allosteric Inhibition of Brain Glycogen Phosphorylase by Neurotoxic Dithiocarbamate Chemicals

Mathieu¹,

Bui²,

Petit³

et al. 2017

Journal of Biological Chemistry

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Edited by Ruma BanerjeeDithiocarbamates (DTCs) are important industrial chemicals used extensively as pesticides and in a variety of therapeutic applications. However, they have also been associated with neurotoxic effects and in particular with the development of Parkinson-like neuropathy. Although different pathways and enzymes (such as ubiquitin ligases or the proteasome) have been identified as potential targets of DTCs in the brain, the molecular mechanisms underlying their neurotoxicity remain poorly understood. There is increasing evidence that alteration of glycogen metabolism in the brain contributes to neurodegenerative processes. Interestingly, recent studies with N,N-diethyldithiocarbamate suggest that brain glycogen phosphorylase (bGP) and glycogen metabolism could be altered by DTCs. Here, we provide molecular and mechanistic evidence that bGP is a target of DTCs. To examine this system, we first tested thiram, a DTC pesticide known to display neurotoxic effects, observing that it can react rapidly with bGP and readily inhibits its glycogenolytic activity (k inact ‫؍‬ 1

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A chemoproteomic platform to quantitatively map targets of lipid-derived electrophiles

Cited by 268 publications

References 44 publications

An Isozyme-specific Redox Switch in Human Brain Glycogen Phosphorylase Modulates Its Allosteric Activation by AMP

An Isozyme-specific Redox Switch in Human Brain Glycogen Phosphorylase Modulates Its Allosteric Activation by AMP

Activation of the Classical Mitogen-Activated Protein Kinases Is Part of the Shiga Toxin-Induced Ribotoxic Stress Response and May Contribute to Shiga Toxin-Induced Inflammation

Molecular Mechanisms of Allosteric Inhibition of Brain Glycogen Phosphorylase by Neurotoxic Dithiocarbamate Chemicals

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